Fast dissolving tablet

ABSTRACT

The present invention relates to processes for the preparation of tablets which dissolve rapidly in the mouth and provide an excellent mouthfeel. The tablets of the invention comprise a compound which melts at about 37° C. or lower, have a low hardness, high stability and generally comprise few insoluble disintegrants which may cause a gritty or chalky sensation in the mouth. Convenient and economically feasible processes by which the tablets of the invention may be produced are also provided.

[0001] This application is a Continuation in Part of U.S. patentapplication Ser. No. 09/731,479 filed Dec. 6, 2000, entitled “FastDissolving Tablet,” the contents of which are incorporated herein intheir entirety to the extent that it is consistent with this inventionand application.

BACKGROUND OF THE INVENTION

[0002] 1. Field of the Invention

[0003] The current invention relates to tablets of low hardness but goodphysical stability, in particular fast dissolving tablets that can bemade at very low compression force, yet have acceptable stability, andmethods for preparing such tablets.

[0004] 2. Description of the Related Art

[0005] Several processes are presently available by which a tablet,which dissolves quickly in the mouth, may be formulated. However,various disadvantages are associated with these currently availablemethods for producing fast dissolving tablets. For example the additionof high levels of disintegrants is disclosed by Cousin et al. (U.S. Pat.No. 5,464,632). Cousin et al. add two disintegrants to the disclosedtablet formulations, for example 16% starch 1500 and 13.3%crossprovidone. The oral-disintegration time of these tablets is 35seconds to 45 seconds. However, tablets including high levels ofdisintegrants have a chalky or dry feel when placed in the mouth.

[0006] Another process for producing fast dissolving tablets involvesfreeze drying or lyophilizing solutions or suspensions of an activeingredient and matrix forming excipients. Pebley et al. (U.S. Pat. No.5,298,261) disclose freeze-drying a slurry or paste comprising an activeingredient and excipients placed in blister packets. Humbert-Droz et al.(WO 97/36879) disclose vacuum drying, at room temperature or a slightlyelevated temperature, a suspension including the active drug, a sugaralcohol, PEG 6000, talc, sweeteners and flavors in preformed blisters.The disadvantages of the freeze drying or vacuum drying methods are time(very slow process), cost of the equipment (not done on conventionaltablet manufacturing equipment), and that it is limited to low doseactives.

[0007] Fast-dissolving tablets may also be formulated by the inclusionof effervescent coupled compounds. Wehling et al. (U.S. Pat. No.5,178,878 and WO 91/04757) disclose the addition of an effervescentcouple (such as sodium bicarbonate and citric acid) to a tablet.Exposure of the tablet to moisture results in contact and chemicalreaction between the effervescent couple which leads to gas productionand tablet disintegration. For this reason, tablets which includeeffervescent pairs are highly sensitive to moisture and have anunpleasant mouthfeel.

[0008] Tablets formed by compression under low compression force alsodissolve more rapidly than tablets formed by high compression force.However, tablets produced by these processes have a high degree offriability. Crumbling and breakage of tablets prior to ingestion maylead to uncertainty as to the dosage of active ingredient per tablet.Furthermore, high friability also causes tablet breakage leading towaste during factory handling.

[0009] The present invention addresses these and other problemsassociated with the prior art. The invention provides fast-dissolvingtablets of low hardness, low friability and high stability which havethe added advantage of cost-effective methods of manufacture and areamenable to established manufacturing and packaging methods. Inparticular, the fast-dissolving tablets of the invention melt rapidly inthe mouth and provide an excellent mouth feel.

SUMMARY OF THE INVENTION

[0010] The present invention advantageously provides compositions andmethods for preparing a fast dissolving tablet of low hardness but goodphysical stability that can be made at very low compression force.

[0011] Thus, the invention provides a tablet comprising a low meltingpoint compound that melts or softens at or below 37° C., a water solubleexcipient, and an active ingredient. Preferably, the low melting pointcompound comprises from about 0.01% to about 20% (wt/wt) of thecomposition (e.g., 0.01, 0.1, 1, 2.5, 5, 7.5, 10, 12, 14, 16, 18, or 20%(wt/w). Preferably, the tablet has a hardness of about 3 kP or less,more preferably about 2 kP or less, and still more preferably about 1 kPor less. Preferably, the minimum hardness of the tablet is about 0.1 kP,although lower values, including 0.05 kP, are possible. When establishedmanufacturing and packaging methods are used the low melting pointcompound preferably comprises about 0.01% to about 2% (wt/wt) of thecomposition and the tablet hardness is preferably about 1.0 to about 2.0kP and more preferably between about 1.2 and about 1.5 kP.

[0012] The invention further provides a method of producing a tabletcomposition. The method comprises combining an active agent (also termed“active ingredient” or “active”) with a fast dissolving granulation. Thefast dissolving granulation comprises a low melting point compound and awater soluble excipient. Preferably, the low melting point compound ispresent in an amount that will yield values (i.e., content thereof) ofabout 0.01% to about 20% (wt/wt) in a final tablet composition (e.g.,0.01, 0.1, 1, 2, 2.5, 5, 7.5, 10, 12, 14, 16, 18, or 20% (wt/wt)).

[0013] The accompanying Detailed Description, Examples and Drawingsfurther elaborate the invention and its advantages.

BRIEF DESCRIPTION OF THE DRAWINGS

[0014]FIG. 1 shows a graph of tablet hardness as a function ofcompression force for tablets of the invention prepared by a meltgranulation process (diamonds), and tablets prepared by directcompression (squares).

[0015]FIG. 2 shows a graph of friability as a function of tablethardness; “Number of Rotations” indicates a number of rotations in aFriabilator which occur before a tablet breaks. Tablets prepared by meltgranulation (diamonds) or by direct compression (squares) wereevaluated.

[0016]FIG. 3 shows a graph of time onset of disintegration (T1) as afunction of compression force for tablets of the invention (diamonds)and for tablets formed by direct compression (squares).

[0017]FIG. 4 shows a graph of disintegration time (T2) as a function ofcompression force for tablets of the invention (diamonds) and fortablets formed by direct compression (squares).

[0018]FIG. 5 shows a graph of disintegration time as a function of thefriability (as measured by the number of rotations in a Friabilatorbefore a first tablet breaks) for tablets of the invention (diamonds)and for tablets formed by direct compression (squares).

[0019]FIG. 6 shows a graph of time to dissolve (mean of disintegrationtime in seconds for 34 samples of a tablet of the invention (MG), twotypes of tablets formed by direct compression (DC1 and DC2), and acommercial fast dissolving tablet (KIDTAB®).

[0020]FIG. 7 shows a graph of grittiness score (adjusted mean determinedby least squares from ANOVA). Subjects scored this sensory attribute ona scale of 1 (low grittiness) to a 9 (high grittiness). Tablets were asdescribed for FIG. 6.

[0021]FIG. 8 shows a graph of chalkiness score (adjusted mean determinedby least squares from ANOVA). Subjects scored this sensory attribute ona scale of 1 (low chalkiness) to a 9 (high chalkiness). Tablets weredescribed for FIG. 6.

[0022]FIG. 9 shows a graph of overall preference ranking for eachproduct (as described in FIG. 6), represented by the percentage ofsubjects ranking each product 1^(st), 2^(nd), 3^(rd), or 4^(th)

DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS

[0023] The current invention provides fast dissolving tabletformulations that can be formed by compression into a conventionaltablet. Tablet friability is lower than conventional fast dissolvingtablets prepared by low compression. The fast dissolving tablet has atleast one compound (or “component”) which partially or fully melts orsoftens at or below body temperature and a water soluble excipient.Surprisingly, it has been found that use of the component whichpartially or fully melts below body temperature in an amount of about0.01% to about 2.5% wt. in the tablet provides for a fast dissolvingtablet composition that is conveniently amenable to established tabletmanufacturing processes and equipment and to established packagingmethods. Amenable to established tablet and manufacturing processes andequipment is taken to mean that the composition (which forms the tablet)may be processed with conventional manufacturing equipment with minimaloccurrence of malformed product and/or the need for special equipmentmaintenance procedures The low melting point compound may be hydrophilicor hydrophobic. The tablets of the invention may also include an activeingredient and may also include one or more disintegrants, flavors,colorants, sweeteners, souring agents, glidants or lubricants.

[0024] The hardness of the tablets is low (less than or equal to about 3kP), preferably less than or equal to about 2 kP, and more preferablyless than or equal to about 1 kP, with a minimum hardness of about 0.1kP (e.g., 0.05, 0.07, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0,1.3, 1.6, 1.9, 2.0, 2.1, 2.3, 2.5, 2.7, 2.8, or 3.0 kP). In embodimentswell suited to established manufacturing and packaging methods, thetablet hardness is preferably about 1.2 to about 1.5 kP. In otherembodiments, hardness ranges from about 0.2 to about 1 kP. Attributessuch as (1) fast stable dissolution; (2) good tablet mouth feel; and (3)good tablet physical stability are of greater importance than minimumand maximum values of tablet hardness. Nevertheless, the tablets aresomewhat pliable, and are less fragile than conventional tablets thathave the same crushing strength. The tablets have an excellent mouthfeelresulting from the low melting point component which melts or softens inthe mouth to produce a smooth feel and masks the grittiness of insolubleingredients. Unlike other fast dissolving tablets, the disintegration ofthis fast dissolving tablet occurs by a combination of melting,disintegration of the tablet matrix, and dissolution of water solubleexcipient. Therefore, a dry feels does not occur. Disintegration time is10 to 30 seconds (e.g., 10, 12, 14, 16, 18, 20, 22, 24, 26, 28 or 30seconds), depending on the tablet size and amount of insolubleingredients, e.g., coated active. Even though the tablet contains a lowmelting point ingredient, it is relatively stable to high temperatures.Heating the tablet above the melting point of its low melting pointcomponent will not significantly reduce its physical stability.

[0025] The friability of conventional tablets is measured by thepercentage weight loss after a typical friability test (rotating 10tablets in a friability apparatus for 100 rotations). This test is veryharsh for conventional fast dissolving tablets and so cannot be used tomeasure their friability. Fast dissolving tablets made by a prior artmethod of direct compression at low force crumble after a few rotationsin the friability apparatus. Fast dissolving tablets manufactured by themethod in the current invention can withstand 20-50 rotations in thefriability apparatus before any tablet breaks. After 20 rotations, thefriability (% weight lost) is typically less than 1%.

[0026] The term “low melting point compound” may include any ediblecompound which melts or softens at or below 37° C. which is suitable forinclusion in the tablets of the invention. Materials commonly used formanufacturing suppositories usually have a melting point at or justbelow body temperature and can be used in the invention. The low meltingpoint compound can be hydrophilic or hydrophobic.

[0027] Examples of hydrophilic low-melting point compounds include, butare not limited to, polyethylene glycol; the preferred mean molecularweight range of polyethylene glycol for use in the tablets of theinvention is from about 900 to about 1000. Mixtures of polyethyleneglycol with different molecular weights (200, 300, 400, 550, 600, 1450,3350, 8000 or 10,000) are within the scope of the invention if themixture melts or softens at or below 37 degrees celsius.

[0028] Examples of hydrophobic low-melting point compounds include, butare not limited to, low melting point triglycerides, monoglycerides anddiglycerides, semisynthetic glyceride (e.g., EUTECOL®, GELUCIRE®(gatteffosse)), hydrogenated oils, hydrogenated oil derivatives orpartially hydrogenated oils (e.g., partially hydrogenated palm kerneloil and partially hydrogenated cottonseed oil), fatty acid esters suchas myistyl lactate, stearic acid and palmitic acid esters, cocoa butteror its artificial substitutes, palm oil/palm oil butter, and waxes ormixtures of waxes, which melt at 37° C. or below. In preferredembodiments, the hydrogenated oil is Wecobee M. To be effective in thetablet compositions, the low melting point compound must be edible.

[0029] Mono-di-and triglycerides are rarely used as pure components.Hydrogenated vegetable oils and solid or semisolid fats are usuallymixtures of mono-di and triglycerides. The melting point of the fat orhydrogenated vegetable oil is characteristic of the mixture and not dueto a single component. Witepsol (brand name by Condea), Supocire (brandname by Gattefosse), and Novata (brand name by Henkel) are commonly usedin manufacturing suppositories, because they melt at body temperature.All are mixtures of triglycerides, monoglycerides and diglycerides.

[0030] In preferred embodiments, the low melting point compoundcomprises from about 0.01% to about 20%, by weight, of a tabletcomposition (e.g., about 0.01, 0.1, 1, 2.5, 5, 7.5, 10, 12, 14, 15, 16,18 or 20% (wt/wt)). Concentration of low melting point compound in theamount of about 0.01% to about 2% (wt/wt) of the tablet are preferablewhen established manufacturing and packaging methods are used. Thetablets of the present invention also include a water soluble excipient.As used herein, the term “water soluble excipient” refers to a solidmaterial or mixture of materials that is orally ingestible and readilydissolves in water. Examples of water soluble excipients include but arenot limited to saccharides, amino acids, and the like. Saccharides arepreferred water soluble excipients. Preferably, the saccharide is amono-, di- or oligosaccharide. Examples of saccharides which may beadded to the tablets of the invention may include sorbitol, glucose,dextrose, fructose, maltose and xylitol (all monosaccharides); sucrose,lactose, glucose, galatose and mannitol (all disaccharides). In aspecific embodiment, exemplified below, the saccharide is lactose.Preferably, the saccharide is mannitol. Other suitable saccharides areoligosaccharides. Examples of oligosaccharides are dextrates andmaltodextrins. Modified saccharides such as sucralose or otherartificial sweeteners such as saccharin or aspartame, for example, maybe used. Other water soluble excipients may include amino acids such asalanine, arginine, aspartic acid, asparagine, cysteine, glutamic acid,glutamine, glycine, histidine, isoleucine, leucine, lysine, methionine,phenylalanine, proline, serine, threonine, tryptophan, tyrosine andvaline. Glycine and lysine are preferred amino acids.

[0031] In preferred embodiments, the water soluble excipient comprisesfrom about 25% to about 97.5%, by weight, of a tablet composition. Thepreferred range is about 40% to about 80%. For example, tabletcompositions comprising about 25, 30, 35, 40, 45, 50, 55, 60, 65, 70,75, 80, 85, 90, 95 or 97.5%, by weight, of the excipient, e.g.monosaccharide, disaccharide, polysaccharide, modified saccharide,artificial sweetener or mixtures thereof are within the scope of theinvention.

[0032] As used herein, the term “about” (or “approximately”) means aparticular value can have a range acceptable to those of skill in theart given the nature of the value and method by which it is determined.In a specific embodiment, the term means within 50% of a given value,preferably within 20%, more preferably within 10%, and more preferablystill within 5%.

[0033] Active Ingredients

[0034] As used herein, the term “active ingredient” or “active agent”refers to one or more compounds that have some pharmacological property.Accordingly, more than one type of active ingredient compound may beadded to the tablets of the invention. The tablets of the invention maycomprise any active ingredient which may be orally administered to asubject. Tablets including active ingredients in amounts appropriate forthe desired pharmacological properties at the dosage administration canbe formulated. Any amount of active ingredient that does notsignificantly affect beneficial tablet features, such as hardness,friability and mouthfeel are within the scope of the invention. Placebotablets, which lack an “active ingredient” having a known pharmacologicactivity, are also within the scope of the invention. An “activeingredient” of a placebo can be the water soluble excipient (i.e.,lacking any identifiable “active”), a different water soluble compound,or any non-active compound.

[0035] A non-limiting list of acceptable active ingredients may includebut is by no means limited to: 1) antipyretic analgesicanti-inflammatory agents such as indomethacin, aspirin, diclofenacsodium, ketoprofen, ibuprofen, mefenamic acid, dexamethasone,dexamethasone sodium sulfate, hydrocortisone, prednisolone, azulene,phenacetin, isopropylantipyrin, acetaminophen, benzydaminehydrochloride, phenylbutazone, flufenamic acid, mefenamic acid, sodiumsalicylate, choline salicylate, sasapyrine, clofezone or etodolac; 2)antiulcer agents such as ranitidine, sulpiride, cetraxate hydrochloride,gefarnate, irsogladine maleate, cimetidine, lanitidine hydrochloride,famotidine, nizatidine or roxatidine acetate hydrochloride; 3) coronaryvasodilators such as Nifedipine, isosorbide dinitrate, diltiazemhydrochloride, trapidil, dipyridamole, dilazep dihydrochloride, methyl2,6-dimethyl-4-(2-nitrophenyl)-5-(2-oxo-1,3,2-dioxaphosphorinan-2-yl)-1,4-dihydropyridine-3-carboxylate,verapamil, nicardipine, nicardipine hydrochloride or verapamilhydrochloride; 4) peripheral vasodialtors such as ifenprodil tartrate,cinepazide maleate, cyclandelate, cinnarizine or pentoxyfyline; 5) oralantibacterial and antifungal agents such as pencillin, ampicillin,amoxicillin, cefalexin, erythromycin ethylsuccinate, bacampicillinhydrochloride, minocycline hydrochloride, chloramphenicol, tetracyline,erythromycin, fluconazole, itraconazole, ketoconazole, miconazole orterbinafine; 6) synthetic antibacterial agents such as nalidixic acid,piromidic acid, pipemidic acid trihydrate, enoxacin, cinoxacin,ofloxacin, norfloxacin, ciprofloxacin hydrochloride, or sulfamethoxazoletrimethoprim; 7) antipasmodics such as popantheline bromide, atropinesulfate, oxapium bromide, timepidium bromide, butylscopolamine bromide,rospium chloride, butropium bromide, N-methylscopolamine methylsulfate,or methyloctatropine bromidebutropium bromide; 8) antitussive,anti-asthamitic agents such as theophylline, aminophylline,methlephedrine hydrochloride, procaterol hydrochloride, trimetoquinolhydrochloride, codeine phosphate, sodium cromoglicate, tranilast,dextromethorphane hydrobromide, dimemorfan phosphate, clobutinolhydrochloride, fominoben hydrochloride, benproperine phosphate,tipepidine hibenzate, eprazinone hydrochloride, clofedanolhydrochloride, ephedrine hydrochloride, noscapine, carbetapentanecitrate oxeladin tannate, or isoaminile citrate; 9) broncyodilators suchas diprophylline, salbutamol sulfate, cloprenaline hydrochloride,formoterol fumarate, orciprenalin sulfate, pirbuterol hydrochloride,hexoprenaline sulfate, bitolterol mesylate, clenbuterol hydrochloride,terbutaline sulfate, mabuterol hydrochloride, fenoterol hydrobromide, ormethoxyphenamine hydrochloride; 10) diuretics such as furosemide,acetazolamide, trichlormethiazide, methyclothiazide,hydrochlorothiazide, hydroflumethiazide ethiazide, cyclopenthiazide,spironolactone, triamterene, fluorothiazide, piretanide, metruside,ethacrygnic acid, azosemide, or clofenamide; 11) muscle relaxants suchas chlorphensin carbamate, tolperison hydrochloride, eperisonehydrochloride, tizanidine hydrochloride, mephenesin, chlorozoxazone,phenprobamate, methocarbamol, chlormezanone, pridinol mesylate,afloqualone, baclofen, or dantrolene sodium; 12) brain metabolismaltering drugs such as meclofenoxate hydrochloride; 13) minortranquilizers such as oxazolam, diazepam, clotiazepam, medazepam,temazepam, fludiazepam, meprobamate, nitrazepam, or chlordiazepoxide;14) major tranquilizers such as sulpiride, clocapramine hydrochloride,zotepine, chlorpromazinon, haloperidol; 15) β-blockers such as pindolol,propranolol hydrochloride, carteolol hydrochloride, metoprolol tartrate,labetalol hydrochloride, acebutolol hydrochloride, butethanolhydrochloride, alprenolol hydrochloride, arotinolol hydrochloride,oxprenolol hydrochloride, nadolol, bucumolol hydrochloride, indenololhydrochloride, timolol maleate, befunolol hydrochloride, or bupranololhydrochloride; 16) antiarrhythmic agents such as procainamidehydrochloride, disopyramide, ajimaline, quinidine sulfate, aprindinehydrochloride, propafenone hydrochloride, or mexiletine hydrochloride;17) gout suppressants allopurinol, probenecid, colchine, sulfinpyrazone,benzbromarone, or bucolome; 18) anticoagulants such as ticlopidinehydrochloride, dicumarol, or warfarin potassium; 19) antiepilepticagents such as phenytoin, sodium valproate, metharbital, orcarbamazepine; 20) antihistaminics such as chlorpheniramine maleate,cremastin fumarate, mequitazine, alimenazine tartrate, or cycloheptazinehydrochloride; 21) antiemetics such as difenidol hydrochloride,metoclopramide, domperidone, betashistine mesylate, or trimebutinemaleate; 22) hypotensives such as dimethylaminoethyl reserpilinatedihydrochloride, rescinnamine, methyldopa, prazosin hydrochloride,bunazosin hydrochloride, clonidine hydrochloride, budralazine, orurapidin; 23) sympathomimetic agents such as dihydroergotamine mesylate,isoproterenol hydrochloride, or etilefrine hydrochloride; 24)expectorants such as bromhexine hydrochloride, carbocysteine, ethylcysteine hydrochloride, or methyl cysteine hydrochloride; 25) oralantidiabetic agents such as glibenclamide, tolbutamide, or glymidinesodium; 26) circulatory agents such as ubidecarenone or ATP-2Na; 27)iron preparations such as ferrous sulfate or dried ferrous sulfate; 28)vitamins such as vitamin B1, vitamin B2, vitamin B6, vitamin B12,vitamin C, Vitamin A, vitamin D, vitamin E, vitamin K or folic acid; 29)pollakiuria remedies such as flavoxate hydrochloride, oxybutyninhydrochloride, terodiline hydrochloride, or4-diethylamino-1,1-dimethyl-2-butynyl (I)-α-cyclohexyl-α-phenylglycolatehydrochloride monohydrate; 30) angiotensin-converting enzyme inhibitorssuch as enalapril maleate, alacepril, or delapril hydrochloride; 31)anti-viral agents such as trisodium phosphonoformate, didanosine,dideoxycytidine, azido-deoxythymidine, didehydro-deoxythymidine,adefovir, dipivoxil, abacavir, amprenavir, delavirdine, efavirenz,indinavir, lamivudine, nelfinavir, nevirapine, ritonavir, saquinavir orstavudine; 32) high potency analgesics such as codeine, dihydrocodeine,hydrocodone, morphine, dilandid, demoral, fentanyl, pentazocine,oxycodone, pentazocine or propoxyphene; 33) antihistamines such asBrompheniramine maleate; 34) nasal decongestants such asphenylpropanolamine HCl and 35) antacids such as calcium carbonate,calcium hydroxide, magnesium carbonate, magesium hydroxide, potassiumcarbonate, potassium bicarbonate, sodium carbonate, and sodiumbicarbonate. Active ingredients in the foregoing list may also havebeneficial pharmaceutical effects in addition to the one mentioned.

[0036] Other Tablet Ingredients

[0037] The term “tablet” refers to a pharmacological composition in theform of a small, essentially solid pellet of any shape. Tablet shapesmay be cylindrical, spherical, rectangular, capsular or irregular. Theterm “tablet composition” refers to the substances included in a tablet.A “tablet composition constituent” or tablet constituent” refers to acompound or substance which is included in a tablet composition. Thesecan include, but are not limited to, the active and any excipients inaddition to the low melting point compound and the water solubleexcipient(s). An excipient is any ingredient in the tablet except theactive. In addition to the low melting point compound excipients mayinclude, for example, binders, disintegrants, flavorants, colorants,glidants, souring agents and sweeteners.

[0038] For purposes of the present application, “binder” refers to oneor more ingredients added before or during granulation to form granulesand/or promote cohesive compacts during compression. A “binder compound”or “binder constituent” is a compound or substance which is included inthe binder. Binders of the present invention include, at least, the lowmelting point compound.

[0039] Additionally, and optionally, other substances commonly used inpharmaceutical formulations can be included such as flavors (e.g.,strawberry aroma, raspberry aroma, cherry flavor, magnasweet 135, keylime flavor, grape flavor trusil art 5-11815, fruit extracts andprosweet), flavor enhancers and sweeteners (e.g., aspartame, sodiumsaccharine, sorbitol, glucose, sucrose), souring agents (e.g. citricacid), dyes or colorants.

[0040] The tablet may also contain one or more glidant materials whichimprove the flow of the powder blend and minimize tablet weightvariation. Glidants such as silicone dioxide may be used in the presentinvention.

[0041] Additionally, the tablets of the invention may include lubricants(e.g. magnesium stearate) to facilitate ejection of the finished tabletfrom dies after compression and to prevent tablets from sticking topunch faces and each other.

[0042] Any method of forming a tablet of the invention into a desiredshape which preserves the essential features thereof is within the scopeof the invention.

[0043] Tablet Formation

[0044] A preferred method of forming the tablet compositions of theinvention includes preparing a fast dissolving granulation by mixing alow-melting point compound, (preferably a hydrogenated oil, partiallyhydrogenated oil or hydrogenated oil derivative) and a water solubleexcipient, (preferably a saccharide or modified saccharide). The term“fast dissolving granulation” refers to a composition of the low meltingpoint compound and the water soluble excipient prepared for use as agranulation in the manufacture of tablets of the invention. A portion ofthe fast dissolving granulation may then be added to the remainingingredients. However, methods of forming the tablets of the inventionwherein all tablet constituents are combined simultaneously or whereinany combination of tablet constituents are combined separate from theother constituents are within the scope of the invention.

[0045] Granulation end point can be determined visually (visualinspection) or by using a load cell that measures power consumption.Tablet manufacturing and granulation routinely employ both techniques.

[0046] The tablet compositions of the invention can be formed by meltgranulation which is a preferred method. In particular, the meltgranulation can be prepared in a high shear mixer (e.g. high sheergranulation process), low shear mixer or fluid bed granulator. Anexample of high shear mixer is Diosna (this is a brand name by DiosnaDierks & Söhne GmbH). Examples of low shear mixers are various tumblingmixers (e.g., twin shell blenders or V-blender). Examples of fluid bedgranulators are Glatt and Aeromatic fluid bed granulators.

[0047] There are at least three ways of manufacturing the granulation:

[0048] Melting the low melting point ingredient, then combining (e.g.,by spraying) it with the water soluble ingredient(s) (including thewater soluble excipient) in the granulator and mixing until granulesform.

[0049] Loading the water soluble excipient in the granulator andspraying the molten low melting point compound on it while mixing.

[0050] Combining the two (water soluble component (including the watersoluble excipient) and low melting point component) and possibly otheringredients and mixing while heating to a temperature around a higherthan the melting point of the low melting point component until thegranules form.

[0051] After the granulation congeals, it may be milled and/or screened.Examples of mills that can be used are CoMill, Stokes Oscillator (theseare brand names). Any mills that are commonly used for milling tabletgranulations may be used.

[0052] Melt extrusion can be used to form the fast dissolvinggranulation. An example of an extruder that can be used is Nica (a brandname by Niro-Aeromatic). The low melting point compound and the watersoluble saccharide (or other excipient) are mixed and heated in aplanetary mixer bowl (low shear mixer) that is usually part of theextruder. The soft mass is then fed to the extrusion chamber and forcedthrough small holes or orifices to shape it into thin rods or cylinders.After the extruded material congeals it can be milled or spheronizedusing standard equipment. In the spheronization step, the extrudate isdumped onto the spinning plate of the spheronizer and broken up intosmall cylinders with a length equal to their diameter, then rounded byfrictional forces (See, International Journal of Pharmaceutics 1995,116:131-146, especially p. 136).

[0053] Spray congealing or prilling can also be used to form the tabletcompositions of the invention. Spray congealing includes atomizingmolten droplets of compositions which, may include low melting pointcompound, low melting point compound and selected tablet ingredients, orthe entire tablet composition onto a surface. The surface may be aninert mechanical support, a carrier surface or in embodiments in whichthe spray contain droplets only part of the tablet components a secondportion of the tablet composition. Equipment that can be used for spraycongealing includes spray driers (e.g., Nero spray drier) and a fluidbed coater/granulation with top spray (e.g., Glatt fluid bedcoater/granulator). In preferred embodiments, a fast-dissolvegranulation is formed wherein, preferably a water soluble excipient,more preferably a saccharide, is suspended in a molten low melting pointingredient and spray congealed. After spray congealing, the resultingcomposition is allowed to cool and congeal. Following congealing of themixture, it is screened or sieved and mixed with remaining tabletconstituents. Spray congealing processes wherein fast-dissolvegranulations comprising any combination of low melting point compoundand other tablet constituents are melted and spray congealed onto othertablet constituents are within the scope of the present invention. Spraycongealing processes wherein all tablet constituents, including thelow-melting point compound, are mixed, the low melting point compound ismelted and the mixture is spray congealed onto a surface are also withinthe scope of the invention.

[0054] After spray congealing, the mixture may be milled and thencombined with other tablet constituents. Following formation of thefinal tablet composition, the composition may be further processed toform a tablet shape.

[0055] Mixing and milling of tablet constituents during the preparationof a tablet composition may be accomplished by any method which causesthe composition to become mixed to be essentially homogeneous. Inpreferred embodiments the mixers are high-shear mixers such as theDiosna, CoMill or V-Blender.

[0056] Once tablet compositions are prepared, they may be formed intovarious shapes. In preferred embodiments, the tablet compositions arepressed into a shape. This process may comprise placing the tabletcomposition into a form and applying pressure to the composition so asto cause the composition to assume the shape of the surface of the formwith which the composition is in contact. In preferred embodiments, thetablet is compressed into the form at a pressure which will not exceedabout 10 kN, preferably less than 8 kN. For example, pressing thetablets at less than 1, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 7, 8, 9 or10 kN is within the scope of the invention. The tablets of the inventiongenerally have a hardness of about 3 kP or less; preferably the tabletshave a hardness of about 2 kP or less and more preferably about 1 kP orless. For compositions subjected to established manufacturing methodshardness of about 1 to about 2.0 is preferred and harness of about 1.2to about 1.5 is more preferable. In another embodiment, for example,tablets of less than 0.1 kP including tablets of about 0.05, 0.07 kP andtablets of about 0.2, 0.3, 0.4, 0.5, 0.6. 0.7, 0.8, 0.9, 1.0, 1.3, 1.6,1.9, 2.0, 2.1, 2.3, 2.5, 2.7, 2.8, or 3.0 are within the scope of theinvention. Hydraulic presses such as a Carver Press or rotary tabletpresses such as the Stokes Versa Press are suitable means by which tocompress the tablet compositions of the invention.

[0057] Tablets may also be formed by tumbling melt granulation (TMG)essentially as described in Maejima et al. Chemical PharmacologyBulletin (1997) 45(3): 518-524; which is incorporated herein byreference. Tumbling melt granulation can be used for preparing the meltgranulation. It can be done in a tumbling mixer. The molten low meltingpoint compound is sprayed on the crystalline saccharide and powderedsaccharide in the blender and are mixed until granules form. In thiscase, the low melting point ingredient is the binder and the crystallinesaccharide is the seed. An alternative method is to combine the unmeltedlow melting point ingredient, crystalline sugar (e.g., mannitol orlactose) in the tumbling mixer and mix while heating to the meltingpoint of the low melting point binder or higher. The seed should becrystalline or granular water soluble ingredient (saccharide), e.g.,granular mannitol, crystalline maltose, crystalline sucrose, or anyother sugar. An example of tumbling mixers is the twin-shell blender(V-blender), or any other shape of tumbling mixers. Heating can beachieved by circulating heated air through the chamber of the granulatorand by heating the bottom surface of the chamber. As the seed materialand the powdered tablet constitutes circulate the heated chamber, thelow-melting point compound melts and adheres to the seeds. The unmelted,powdered material adheres to the seed-bound, molten low-melting pointmaterial. The spherical beads which are formed by this process are thencooled and screen sifted to remove nonadhered powdered material.

EXAMPLE 1 Fast Dissolving Granulation

[0058] Compositions of Fast Dissolving Granulations. In thesecompositions, the water soluble excipient is a saccharide. As describedabove, the tablets of the invention may be formulated by a methodwherein a fast dissolving granulation, comprising a low melting pointcompound and a water soluble excipient, is mixed separately from othertablet constituents. A portion of the fast dissolving granulation maythen be combined with the other tablet constituents. In this example,several specific examples of fast dissolving granulations are set forth.TABLE 1 Fast dissolving granulation formulations. Fast DissolvingGranulation Low Melting Point Saccharide Composition Compound (amount)(amount) 1 Wecobee M hydrogenated mannitol powder (5 Kg) vegetable oil(1 Kg) 2 Gelucire 33/01 semi- mannitol powder (1 Kg) syntheticglycerides (200 g) 3 Wecobee M (150 g) crystalline maltose (100 g)mannitol powder (750 g) 4 polyethylene glycol fructose powder (400 g)900 (100 g)

[0059] Fast dissolving granulations 1 and 2 were prepared by heating thelow melting point compound to 50° C. At 50° C., Wecobee M and Gelucire33/01 become molten. The molten material was gradually added to themannitol powder in a high shear granulator (Diosna). The granulation wasmixed at high speed. When the granulation end point was reached asdetermined by visual inspection, the granulation was allowed to congeal.The congealed granulation was then milled using a CoMill.

[0060] Granulation 3 was granulated by combining melted Wecobee M withthe mannitol in a high shear mixer (Robot Coupe) and blending until thegranules formed. Granulation 4 was made by combining the melted PEG withfructose powder in a planetary mixer (low shear mixer) and mixing untilthe granules formed. The granulations were allowed to cool, then werescreened.

EXAMPLE 2 Fast Dissolving Ibuprofen Tablets

[0061] The following is an example of a fast dissolving tablet whereinthe active ingredient is ibuprofen. Ingredient Amount (mg tablet) Coatedibuprofen (active ingredient) 121.9 (equivalent to 100 mg ibuprofen)Citric acid (souring agent) 11.0 Magnasweet 135 (sweetening agent) 3.9Aspartame (sweetening agent) 6.5 Cherry flavor (flavoring agent) 7.8Crosscarmellose sodium (disintegrant) 39.0 Silicone dioxide (glidantflow aid) 1.95 Magnesium stearate (lubricant) 3.25 Fast dissolvinggranulation 4 457.9 Total 653.2

[0062] Ingredients were screened, then mixed in a V-blender. Tabletswere compressed using a hydraulic press (Carver Press) at 600 lb (about2.7 kN). The tablets had a hardness of 0.2-0.5 kP and disintegrated inless than 15 seconds.

EXAMPLE 3 Fast Dissolving Antihistamine/Decongestant Tablets

[0063] The following is an example of a fast dissolving tabletcomprising the active ingredients of many common allergy medications,Phenylpropanolamine HCl and Brompheniramine maleate. Ingredient Amount(mg/tablet) Phenylpropanolamine HCI 6.25 (active ingredient)Brompheniramine maleate 1.0 (active ingredient) Citric acid (souringagent) 6.0 Magnasweet 135 (sweetening agent) 1.80 Aspartame (sweeteningagent) 4.5 Cherry flavor (flavoring agent) 3.60 Corn Starch(anti-adherent) 30.0 Silicone dioxide (glidant flow aid) 3.0 Fastdissolving granulation 4 219.25 Magnesium stearate (lubricant) 2.1 Total301.5

[0064] Tablets were compressed on a hydraulic press (Carver Press) atapproximately 3 kN. Tablet hardness was 0.2-0.5 kP and disintegrationtime 10 seconds.

EXAMPLE 4 Fast Dissolving Ibuprofen Tablets

[0065] The following is an example of a fast dissolving tablet whereinthe active ingredient is ibuprofen. Ingredient Amount (mg/tablet) Coatedibuprofen (active agent) 119.0 Citric Acid (souring agent) 20.0Magnasweet 135 (sweetening agent) 7.5 Aspartame (sweetening agent) 7.5Grape flavor Trusil Art 5-11815 5.00 (flavoring agent) Prosweet (flavorand sweetness enhancer) 5.00 Crosscarmellose sodium (enhancer) 20.0 CornStarch, NF (anti-adherent) 40.0 Silicone dioxide (Syloid 244) 5.00(glidant flow aid) Fast dissolving granulation 1 271 Total 500

[0066] Tablets were compressed using a rotary press (Stokes Versa Press)at 3.3.-3.5 kN, resulting in a hardness of 0.2-0.9 kP. In vivodisintegration time was 19 seconds (average of 34 subjects).

[0067] Sensory study: The melt granulation tablets of Example 4 wereevaluated for in vivo disintegration time and mouthfeel in an in-housesensory study. The comparator was Kidtab®, an 80 mg acetaminophen fastdissolving tablet prepared by direct compression. Two other ibuprofenfast dissolving tablets prepared by direct compression were alsoincluded in the study. The study included 34 subjects. The subjects wereasked to record the time for the tablet to completely dissolve in themouth and give scores for mouthfeel attributes and overall liking of theproduct. The melt granulation prototype (based on this invention)performed best on disintegration time (FIG. 6) and mouthfeel attributes(least grittiness (FIG. 7) and least chalkiness (FIG. 8)) and wereranked best on the overall performance by the panelists. The followingtable shows the ranking results of the sensory study on disintegrationtime and mouthfeel attributes: MG is the melt granulation tablet of theinvention. DC1 and DC2 are the two direct compression phototypes.Ranking (1 = best, 4 = worst) Prototype/Product Sensory Attribute DC1 MGKidtab DC2 Time to dissolve (seconds) 2 1 4 3 Grittiness 4 1 2 3Chalkiness 3 1 4 2 Overall Preference 4 1 2 3

[0068] The tablets of the invention were ranked the highest (1, best) inall four categories tested (dissolution time, grittiness, chalkiness andoverall performance) against DC1, DC2 and KIDTAB.

[0069] As illustrated in FIG. 6, the tablets of the invention exhibitedsuperior fast dissolving characteristics as compared to the directcompression tablets which were also evaluated (DC1, DC2 and KIDTAB); theaverage time for the tablet of the invention (MG) to dissolve was 19seconds wherein the time for DC1, DC2 and KIDTAB to dissolve were about20, 22 and 25 seconds, respectively. The tablets of the invention alsoexhibited a mouthfeel which was superior to the DC1, DC2 and KIDTABtablets. FIGS. 7 and 8 indicate the 34 individuals who participated inthe study perceived a lower level of grittiness and chalkinessassociated with the tablets of the invention as compared to the directcompression tablets (DC 1, DC2 and KIDTAB).

[0070] Overall preference was also scored (least squares mean fromANOVA) on a scale from 1 (most preferred) to 9 (least preferred). Asindicated in FIG. 9, the tablet of the invention scored highest (2.11),followed by the KIDTAB® (2.29), and the two direct compression tablets(DC2-2.52, DC1-03.05).

EXAMPLE 5 Fast Dissolving Ibuprofen Tablets

[0071] The following is an example of a fast dissolving tablet whereinthe active ingredient is ibuprofen. Ingredient (mg/tablet) Coatedibuprofen (active agent) 238.0 Citric Acid (souring agent) 17.5Magnasweet 135 (sweetening agent) 9.75 Aspartame (sweetening agent) 9.75Key Lime flavor (flavoring agent) 6.50 Vanilla powder (flavoring agent)0.650 Corn Starch, NF (anti-adherent) 52.0 Silicone dioxide (Syloid 244)6.50 (glidant/flow acid) Sodium stearyl fumarate 4.88 (Pruv) (lubricant)Fast dissolving granulation 1 304 Total 650

[0072] Tablets were compressed using a rotary tablet press (Stokes VersaPress) at 3 kN, resulting in a hardness of 0.35-0.60 kP. In vivodisintegration time was 16 seconds.

EXAMPLE 6 Compressibility and In Vitro Evaluation of Tablets

[0073] To compare fast dissolving tablets of the invention with fastdissolving tablets prepared by direct compression, the following twoexamples were prepared.

[0074] Melt granulation fast dissolving tablet: Ingredient (mg/tablet)Ibuprofen microcaps 119.0 Citric Acid, anhydrous, fine granular 20.0Magnasweet 135 7.5 Aspartame (Nutrasweet) 7.5 Cherry Berry flavor 4.25Sweet AM 2.50 Crosscarmellose sodium 20.0 Corn Starch, NF 40.0 Siliconedioxide (Syloid 244) 5.00 Fast dissolve granulation* 274.25 TOTAL 500

[0075] Direct compression fast dissolving tablet. Ingredient mg/tabletIbuprofen microcaps 119.0 Citric Acid, anhydrous, 20.0 fine granularMagnasweet 135 7.5 Aspartame (Nutrasweet) 7.5 Sweet AM 2.5 Fruit Punchflavor 3.50 Crosscarmellose sodium 20.0 Corn Starch, NF 40.0 Siliconedioxide (Syloid 244) 5.00 Mg Stearate 3.50 Fast Dissolve granulation271.5 TOTAL 500

[0076] Melt granulation tablets and direct compression tablets wereprepared based on the same formula, except that granular mannitol wasused instead of the fast dissolve melt granulation. The compressibilityof the two tablet formulations (melt granulation and direct compression)were compared. The two blends were compressed at different compressionforces and the resulting tablets were evaluated for hardness and invitro disintegration time. Tablet hardness (crushing strength) wasmeasured using a high resolution texture analyzer (Stable Microsystems)with an acrylic cylindrical probe.

[0077] In vitro disintegration was performed in a texture analyzer. Atablet was held on a net that was then attached to a ¼″ stainless stealball probe. The disintegration medium was 5 ml of water in a 50 mlbeaker. The height of water was barely enough to submerge the tablet,and the water temperature was kept at 37±1° C. The texture analyzer wasinstructed to apply a small force (20 g) when the tablet hit the bottomof the beaker. The time for disintegration onset and totaldisintegration time was recorded.

[0078] Compressibility: Fast dissolving tablets in general are soft andneed to be blister-packaged directly off the tablet press. The tabletsmanufactured according to the invention can be compression or wetgranulation. For fast dissolving tablets containing a coated active, itis important to compress at the lowest force possible so that thecoating will not be ruptured under compression. With the meltgranulation approach, tablets that are robust enough to withstandpackaging right off the tablet press were obtained using a compressionforce as low as 2 kN, whereas for a similar direct compressionformulation, acceptable tablets could not be obtained at compressionforces below 5 kN (FIG. 1).

[0079] Hardness and Friability: Although the melt granulation tabletshad a lower hardness compared to direct compression tablets that arecompressed at the same force (FIG. 1), the melt granulation tablets weresomewhat pliable and less fragile. As illustrated in FIG. 2, the softestmelt granulation prototype, with a hardness of about 0.2 kP, was able towithstand at least 9 rotations in the friabilator (friability apparatus)before any tablet breaks. At 0.5 kP, these tablets survived 20-30rotations. Direct compression tablets at about 0.45 kP started breakingafter 4 rotations, while the hardest direct compression prototype withabout 0.9 kP hardness only survived 12 rotations. In the same friabilitytest, Kidtab® tablets (marketed fast dissolving tablets prepared bydirect compression) started breaking after 5-10 rotations. The averagehardness of Kidtab tablets was 1.8 kP. Moreover, at the end of the test,the direct compression tablets showed more chipping around the edgesthan melt granulation prototypes. Direct compression tablets withhardness greater than 1 kP were not fast dissolving (took 1 minute ormore to dissolve in the mouth of a subject).

[0080] In vitro Disintegration: The onset of disintegration was fasterfor the melt granulation prototypes compared to direct compressionprototypes prepared at the same compression force (FIG. 3). Furthermore,the total time for in vitro disintegration was dependent on compressionforce regardless of the formulation (FIG. 4). We obtained acceptabletablets from the melt granulation processing low compression force.Direct compression tablets could not be obtained at the same compressionforce. Therefore, for tablets with similar friability, the meltgranulation approach produced faster disintegration time (FIG. 5).

[0081] The melt granulation was less sensitive to small changes incompression force, whereas for the direct compression formulation, bothhardness and onset of disintegration increased sharply with increasingthe compression force (FIGS. 1 and 3).

EXAMPLE 7 Example of Melt Granulation Tablets with Higher Hardness

[0082] Ingredient mg/tablet Ibuprofen microcaps 121.9 (encapsulatedibuprofen) Citric Acid, anhydrous, fine granular 11.0 Magnasweet 135 4.0Aspartame (Nutrasweet) 6.0 Cherry flavor 6.0 Sweet AM 0.5Crosscarmellose sodium 45.0 Corn Starch, NF 40.0 Silicone dioxide(Syloid 244) 2.50 Fast dissolve granulation 263.1 TOTAL 500

[0083] Tablets were compressed on Stokes Versapress. Compression forcewas not recorded. Tablet hardness was 1.5 kP. The tablets had afriability of less than 1.0% after 50 rotations in the friabilator, i.e,lost less than 1% of their initial weight and no tablet broke. Mean invivo disintegration time was 25.8 seconds (12 subjects were asked totake the tablets and record the time it takes for the tablet tocompletely dissolve without chewing).

EXAMPLE 8 Example of Melt Granulation Tablets Amendable to EstablishedTablet Manufacturing Process and Packaging Methods

[0084] Ingredient mg/tablet Composition 1 Ibuprofen microcaps 238.0Sucralose 5.6 Citric acid 28.0 Lemon-lime flavor 1.4 Crosscamellose 28.0Mannitol SD200 315.0 Corn starch 42.0 CabOSil 7.0 Fast DissolveGranulation* 35.0 Composition 2 Ibuprofen microcaps 238.0 Sucralose 5.6Citric acid 28.0 Lemon-lime flavor 1.4 Crosscamellose 28.0 MannitolSD200 280.0 Corn starch 42.0 CabOSil 7.0 Fast Dissolve Granulation* 70.0Composition 3 Ibuprofen microcaps 238.0 Sucralose 5.6 Citric acid 28.0Lemon-lime flavor 1.4 Crosscamellose 28.0 Mannitol SD200 297.5 Cornstarch 42.0 CabOSil 7.0 Fast Dissolve Granulation* 52.5

[0085] The present invention is not to be limited in scope by thespecific embodiments described herein. Indeed, various modifications ofthe invention in addition to those described herein will become apparentto those skilled in the art from the foregoing description and theaccompanying figures. Such modifications are intended to fall within thescope of the appended claims.

[0086] It is further to be understood that all values are approximate,and are provided for description.

[0087] Patents, patent applications, publications, product descriptions,and protocols are cited throughout this application, the disclosures ofwhich are incorporated herein by reference in their entireties for allpurposes.

What is claimed:
 1. A tablet comprising a low melting point compoundthat melts or softens at or below 37° C., a water soluble excipient andan active ingredient, wherein the low melting point compound comprisesfrom about 0.01% to about 2.5% (wt/wt) of the tablet, and wherein thetablet has a hardness of about 2.0 or lower.
 2. The tablet of claim 1,wherein the water soluble excipient comprises about 25% to about 97.5%(wt/wt) of the tablet.
 3. The tablet of claim 1 wherein the watersoluble excipient comprises about 40% to about 85% (wt/wt) of thetablet.
 4. The tablet of claim 1 wherein the water soluble excipient isa saccharide.
 5. The tablet of claim 4 wherein the saccharide is one ormore substance selected from the group consisting of maltose, fructose,sucrose, lactose, glucose, galactose, xylitol, sorbitol, dextrates,maltodextrins and mannitol.
 6. The tablet of claim 1 wherein the watersoluble excipient is sucralose.
 7. The tablet of claim 1 wherein thewater soluble excipient is aspartame.
 8. The tablet of claim 1 furthercomprising one or more components selected from the group consisting ofa disintegrant, a colorant, a sweetener, a souring agent, a glidant, abinder, a lubricant and a flavorant.
 9. The tablet of claim 1 whereinthe low melting point compound is one or more compounds selected fromthe group consisting of hydrogenated oil, polyethylene glycol, lowmelting point triglycerides, low melting point diglycerides, low meltingpoint monoglycerides, synthetic glycerides, fatty acid esters,semisynthetic glycerides, partially hydrogenated oil, palm oil, palmbutter, wax and cocoa butter.
 10. The tablet of claim 9 wherein thehydrogenated oil or partially hydrogenated oil is a vegetable oil. 11.The tablet of claim 9 wherein the low melting point compound comprises amixture of a low melting point monoglyceride, a low melting pointdiglyceride and a low melting point triglyceride.
 12. The tablet ofclaim 9 wherein the low melting point compound is a partiallyhydrogenated oil and wherein the partially hydrogenated oil is one ormore substances selected from the group consisting of partiallyhydrogenated palm kern oil and partially hydrogenated cotton seed oil.13. The tablet of claim 9 wherein the hydrogenated oil is a hydrogenatedvegetable oil.
 14. The tablet of claim 9 wherein the low melting pointcompound is a fatty acid ester and the fatty acid ester is one or morecompounds selected from the group consisting of stearic acid ester,palmitic acid ester and myristyl lactate ester.
 15. A method ofproducing a tablet composition, which comprises combining an activeagent with a fast dissolving granulation, wherein the fast dissolvinggranulation comprises a low melting point compound and a water solubleexcipient.
 16. The method of claim 15, which further comprises combiningwith the active agent and the fast dissolving granulation one or morecomponents selected from the group consisting of a disintegrant, acolorant, a sweetener, a lubricant, a souring agent, a glidant, a binderand a flavorant.
 17. The method of claim 15, which further comprisesmolding the tablet composition into a tablet form.
 18. The method of 15,wherein the fast dissolving granulation is prepared by high sheergranulation.
 19. The method of claim 18 wherein the low melting pointcompound is molten.
 20. The method of claim 19 wherein the fastdissolving granulation is prepared by spraying the molten low meltingpoint compound onto the water soluble excipient and allowing theresulting composition to congeal.
 21. The method of claim 19 wherein thefast dissolving granulation is prepared by suspending the water solubleexcipient in molten low melting point compound and spray congealing theresulting composition.
 22. The method of claim 19 wherein the tabletcomposition is made by a method comprising extruding the compositioncomprising the active agent and the fast dissolving granulation througha nozzle and allowing the resulting composition to congeal.
 23. Themethod of claim 19 wherein the water soluble excipient is one or moresaccharides selected from the group consisting of maltose, fructose,sucrose, lactose, glucose, galactose, xylitol, sorbitol, and mannitol.24. The method of claim 19 wherein the water soluble excipient is anartificial sweetener.
 25. The method of claim 19 wherein the watersoluble excipient is sucralose.
 26. The method of claim 19 wherein thelow melting point compound is one or more compounds selected from thegroup consisting of hydrogenated oil, polyethylene glycol, low meltingpoint triglycerides, low melting point diglycerides, low melting pointmonoglycerides, synthetic glycerides, fatty acid esters, semisyntheticglycerides, partially hydrogenated oil, palm oil, palm butter, wax andcocoa butter.
 27. The method of claim 19 which comprises congealing amixture comprising molten low melting point compound and the watersoluble excipient.
 28. The method of claim 27, which further comprisesgranulating the congealed mixture by a method selected from the groupconsisting of sifting the congealed mixture through a screen and millingthe congealed mixture.
 29. The method of claim 28 which furthercomprises molding the granulated mixture into a tablet shape.
 30. Aplacebo tablet comprising a low melting point compound that melts orsoftens at or below 37° C. and a water-soluble excipient.
 31. The tabletof claim 30 wherein the low melting point compound comprises from about0.01% to about 2.5% (wt/wt) of the composition and wherein the tablethas a hardness of about 1 to about 2 kP or lower.